Although primary lateral sclerosis (PLS) is generally considered to be a motor neuron disorder, its relationship to amyotrophic lateral sclerosis (ALS) and other motor neuron disorders is uncertain. PLS differs from ALS in its duration, with a median survival of more than a decade, in contrast to the median survival of 3-5 years in ALS. The long survival is closely linked to the restriction of disease to the corticospinal, or upper motor neurons, of the brain. We carried out a longitudinal study in PLS patients that showed that once each body region exhibited symptoms, measures of clinical severity of that region declined more rapidly in the first years and subsequently stabilized without continued progression. This finding suggests that loss of corticospinal input may progress in an intermittent fashion. It also indicates that progression is not linear, arguing against using the slope of clinical decline as an outcome in future clinical trials and highlighting the need for biological markers of disease activity. We have completed a multi-year cross-sectional study to evaluate the hypothesis that ALS and PLS are variants of a common neurodegenerative process that differ phenotypically because of regional differences in pathology. We first looked for overlap and differences in clinical dysfunction corresponding to non-motor cortical regions in PLS and ALS patients with similar extents of upper motor neuron dysfunction. Neuropsychological tests and psychiatric assessments showed that cognitive impairment is less common in PLS, and that PLS patients have a modestly greater extent of depression compared to ALS patients. To correlate clinical measures to regional anatomical measures, diffusion tensor MRI imaging and measures of cortical thickness have been obtained in ALS and PLS patients and healthy age-matched controls. We previously showed that quantitative measures of the corticospinal tract can be made from DTI images with good intra- and inter-rater reliability and test-retest reliability in controls. We are currently completing analysis of these data and are obtaining longitudinal imaging studies on a subset of the PLS and ALS patients in the cross-sectional study.